SEARCH · PubMed Health

Results for “Endophenotypes”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2004

Discovering endophenotypes for major depression.

The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

Affect↗

PubMed2006

The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes.

The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be "neurocognitive" and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.

Cognition Disorders↗

PubMed2004

The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder.

OBJECTIVE: Efforts to identify genetic loci for bipolar disorder (BPD) have thus far proved elusive. The identification of processes mediating between genotype and phenotype (endophenotypes) may help resolve the carrier status of family members in genetic studies of polygenetic disorders with imperfect penetrance, such as BPD. We reviewed the literature to determine if neuropsychological measures could be used as effective endophenotypes to aid molecular genetic studies searching for genes predisposing to BPD. METHODS: Four prerequisites for endophenotypic markers are described, and a critical review of relevant literature was undertaken to determine if neurocognitive measures satisfy these four requirements in BPD. RESULTS: We found evidence that executive functions and declarative memory may be candidate neurocognitive endophenotypes for BPD. However, we cannot exclude other areas of cognition as being affected by BPD susceptibility genes, given the limits of the current knowledge of the neuropsychology of BPD. In particular, the paucity of studies measuring cognition in healthy relatives of BPD patient limits conclusion regarding familial aggregation of particular neurocognitive deficits (i.e. attention). Furthermore, the effects of clinical state and/or medication usage on cognitive functioning in BPD probands should be further explored. CONCLUSIONS: Molecular genetic studies of BPD may benefit from the application of select neuropsychological measures as endophenotypic markers. The use of these markers, once defined, may improve power for detecting genes predisposing to BPD and may help to better define diagnostic criteria.

Bipolar Disorder↗

PubMed2006

Personality: is it a viable endophenotype for genetic studies of bipolar affective disorder?

Progress in identifying the genetic basis of bipolar affective disorder has been disappointing, most probably because of the genetic and phenotypic heterogeneity of the condition. These setbacks have led to the adoption of alternative strategies such as the use of endophenotypes or intermediate traits to identify those individuals at genetic risk for developing the disorder. Gottesman and Gould [Am J Psychiatry (2003), 160:636], in a review of the endophenotypic concept, have suggested five criteria that should be characteristic of a trait in order for it to qualify as an endophenotype. These five criteria are used in order to assess the viability of using personality traits as endophenotypes for genetic analyses of bipolar disorder. A review of the literature suggests that certain personality traits or temperaments are associated with the illness in a state independent manner, that personality is at least partly heritable, and that various temperaments aggregate in the non-affected relatives of bipolar probands. Nevertheless, it is unclear whether specific personality traits co-segregate with affectively ill individuals. We conclude that personality profiling of probands and their relatives may facilitate molecular genetic work, but given the fact that personality is itself a complex trait, its use as an endophenotype has certain limitations.

Bipolar Disorder↗

PubMed2005

Neurocognitive function as an endophenotype for genetic studies of bipolar affective disorder.

The genetic basis of bipolar affective disorder remains opaque despite years of intensive investigation. One of the most serious difficulties for genetic research is the enormous phenotypic heterogeneity of psychiatric illnesses. As a response to this problem, geneticists have searched for alternative strategies to identify those individuals at genetic risk for developing the disorder. One approach is to use endophenotypes or intermediate traits. Gottesman and Gould (2003), in their discussion of endophenotypes, suggest five criteria that should be characteristic of a trait in order for it to qualify as an endophenotype. These five criteria are used in order to assess the viability of using measures of neuropsychological dysfunction as endophenotypes for genetic studies of bipolar disorder. A review of the literature suggests that executive dysfunction is characteristic of people with bipolar disorder in both the acute and chronic stages of the illness, that neurocognitive function is influenced by genetic factors and that neuropsychological deficits have been reported in the nonaffected relatives of bipolar probands. Nevertheless, it is unclear whether neuropsychological dysfunction co-segregates with affectively ill individuals. We conclude that the use of neurocognitive markers of bipolar illness suffers from a number of serious drawbacks but given the absence of more appropriate endophenotypes, the neuropsychological profiling of probands and their relatives may nevertheless prove to be a worthwhile exercise.

Bipolar Disorder↗

PubMed2005

Genetic bases for endophenotypes in psychiatric disorders.

This article reviews the concept of an endophenotype, with particular reference to heritability as well as diagnostic specificity. An endophenotype need not be heritable, for example, the possible influence of in utero viral infections for schizophrenia. However, heritability is a useful characteristic for a potential endophenotype, as it can be studied in relation to a plausible candidate gene. It should be noted that the traditional methods of demonstrating heritability, eg, twin studies, can be supplemented with DNA sequence studies, suggesting heritability. Endophenotypes need not be specific to a given nosological class of psychiatric disorders, as these classes do not reflect biological categories. Evidence for two useful schizophrenia endophenotypes, the P50 abnormalities and cognitive deficits, is summarized.

Cognition Disorders↗

PubMed2006

Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage.

The identification of autism susceptibility genes has been hampered by phenotypic heterogeneity of autism, among other factors. However, the use of endophenotypes has shown preliminary success in reducing heterogeneity and identifying potential autism-related susceptibility regions. To further explore the utility of using language-related endophenotypes, we performed linkage analysis on multiplex autism families stratified according to delayed expressive speech and also assessed the extent to which parental phenotype information would aid in identifying regions of linkage. A whole genome scan using a multipoint non-parametric linkage approach was performed in 133 families, stratifying the sample by phrase speech delay and word delay (WD). None of the regions reached suggested genome-wide or replication significance thresholds. However, several loci on chromosomes 1, 2, 4, 6, 7, 8, 9, 10, 12, 15, and 19 yielded nominally higher linkage signals in the delayed groups. The results did not support reported linkage findings for loci on chromosomes 7 or 13 that were a result of stratification based on the language delay endophenotype. In addition, inclusion of information on parental history of language delay did not appreciably affect the linkage results. The nominal increase in NPL scores across several regions using language delay endophenotypes for stratification suggests that this strategy may be useful in attenuating heterogeneity. However, the inconsistencies in regions identified across studies highlight the importance of increasing sample sizes to provide adequate power to test replications in independent samples.

Autistic Disorder↗

PubMed2007

Adjudicating neurocognitive endophenotypes for schizophrenia.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty-nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.

Adolescent↗

PubMed2006

Incorporating endophenotypes into allele-sharing based linkage tests.

For a genetic study in which there are concordant and discordant sibpairs for a complex disease trait and the measurements of other endophenotypes/intermediate phenotypes for each of the individuals are also available, we describe an allele-sharing based multipoint linkage test that utilizes nonparametrically the additional endophenotypes/intermediate phenotypes. The usefulness of this method is evaluated in simulation studies, which show that the gain in power is influenced by not only the endophenotypic value but also the correlation between the diagnosis-based phenotype and the endophenotype. In addition to reporting p values, our method also provides an index C(E), derived from the coefficients of the weight function associated with the endophenotype in the proposed statistic, to indicate the relevance of a specific endophenotype/intermediate phenotype in the genetic study. The simulation study indicates that a larger power, in general, corresponds to a larger value of the index C(E). The index C(E) is thus suggested as a quantity to be used in the choice of endophenotypes in linkage study. Data from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) are used to illustrate the method.

Adult↗

PubMed2004

[Endophenotype--a new concept for biological characterization of psychiatric disorders].

In the field of psychiatric genetics, the concept of endophenotypes is presently receiving high popularity. Current difficulties in the search for susceptibility genes of complex diseases have been attributed to the etiological heterogeneity of the clinical, psychopathologically defined phenotype of the disease. Neurobiological correlates of the disease which are genetically influenced and stable over time are considered to be more promising targets of phenotypes. They are more directly influenced by gene effects and presumably defined by a genetic determination which is less complex than the phenotype of the disorder. The endophenotype strategy has already been successful in complex disorders of other areas in medicine, including alcoholism and late-onset Alzheimer's disease. For schizophrenia, a series of endophenotypes for molecular/genetic investigation has been suggested, but the concept "endophenotype" also provides a basis for biological classification of mental disorders.

Alcoholism↗

PubMed2005

Alcoholism: the dissection for endophenotypes.

Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.

Alcoholism↗

PubMed2006

Early visual sensory deficits as endophenotypes for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives.

CONTEXT: The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests. OBJECTIVE: Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability. DESIGN, SETTING, AND PARTICIPANTS: Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. RESULTS: Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives. CONCLUSIONS: Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

Adolescent↗

PubMedDate not supplied

P300 event-related potential amplitude as an endophenotype of alcoholism--evidence from the collaborative study on the genetics of alcoholism.

There is substantial information supporting the role of genetic factors in the susceptibility for alcohol dependence. However, the identification of specific genes that contribute to this predisposition has proven elusive, although several theoretically relevant candidates, e.g. DRD2 or 5-HT(1B), have been considered. The difficulty in identifying specific genes may be related to the clinical heterogeneity of the disorder resulting in a poorly defined phenotype for genetic analysis. An alternative approach to the use of a diagnostic phenotype for identifying alcoholism susceptibility genes may lie in the examination of the neurobiological correlates of the disorder, the so-called endophenotypes. One possible endophenotype of alcohol dependence may be related to the P300 waveform of the event-related brain potential (ERP). Using data obtained from the Collaborative Study on the Genetics of Alcoholism (COGA), a multi-site family-based study, the utility of P300 amplitude as an endophentype was examined. Differences in P300 amplitude were found between alcoholics and nonalcoholics, between unaffected relatives of alcoholics and relatives of controls, as well as between unaffected offspring of alcoholic fathers and offspring of controls. A genetic analysis indicated that attributes of the P(3) ERP waveform are heritable, and a quantitative trait locus analysis found linkage to several chromosomal regions. These data provide significant support for P300 as an endophenotype for alcohol dependence.

Alcoholism↗

PubMed2005

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.

Adoption↗

PubMed2006

Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder?

BACKGROUND: Both genetic and environmental factors are involved in the etiology of bipolar disorder; however, biological markers for the transmission of the bipolar genotype ("endophenotypes") have not been found. Autoimmune thyroiditis with raised levels of thyroperoxidase antibodies (TPO-Abs) is related to bipolar disorder and may be such an endophenotype. This study was intended to examine whether autoimmune thyroiditis is related to the disease itself, to the (genetic) vulnerability to develop bipolar disorder, or both. METHOD: Blood was collected from 22 monozygotic (MZ) and 29 dizygotic (DZ) bipolar twins and 35 healthy matched control twins to determine TPO-Abs. RESULTS: The TPO-Abs were positive in 27% of the bipolar index twins, 29% of the monozygotic bipolar cotwins, 27% of the monozygotic nonbipolar cotwins, 25% of the dizygotic bipolar cotwins, 17% of the dizygotic nonbipolar cotwins, and in 16% of the control twins. Repeated measures analysis of covariance on log-transformed absolute TPO-Abs values revealed significantly increased mean TPO-Abs levels in discordant twin pairs as compared with healthy twin pairs, whereas no difference was found between bipolar patients and their (discordant) nonbipolar cotwins. CONCLUSIONS: This study shows that autoimmune thyroiditis is related not only to bipolar disorder itself but also to the genetic vulnerability to develop the disorder. Autoimmune thyroiditis, with TPO-Abs as marker, is a possible endophenotype for bipolar disorder.

Adult↗

PubMed2006

Emotional endophenotypes in evolutionary psychiatry.

Evolutionary psychiatry emerged from the conceptual successes of sociobiology and evolutionary psychology. It will need to avoid the many mistakes that biology-free Evolutionary Psychology has been prey to. It should not ignore the wealth of information that exists between the phenotypic expression of symptoms and the genotypic sources of core brain/mind processes that are disrupted in psychiatric disorders. Syndromal-conceptual thinking has become a barrier to illuminating the biological sources of psychiatric disorders. Endophenoytpic-biomarker approaches now offer robust alternatives for generating linkages between psychiatrically relevant psychological changes and the neurobiological infrastructure of disordered mentation. Here I summarize recent advances in endophenotypic thinking in biological psychiatry, and suggest that various core emotional-affective processes may be among the most important endophenotypes that need to be clarified at both neurobiological and genetic levels of analysis. To this end, I discuss strategies to link basic emotional processes that are commonly imbalanced in psychiatric disorders to neuroanatomical, neurochemical, neurophysiology, and molecular genetic levels of analysis. Conjoint animal behavioral-genetic and gene expression, microarray analyses can clarify a variety of key emotional endophenotypes and thereby provide a coherent infrastructure for psychiatric systematics. To further clarify the neurobiological dimensions of psychiatric disorders, we must also focus on psychosocial and environmental stress vectors that converge to create imbalanced emotional and motivational brain activities of psychiatric significance.

Animals↗

PubMed2006

Comparison of three computer-administered cognitive tasks as putative endophenotypes of schizophrenia.

It has been repeatedly demonstrated that individuals with schizotypal personality features (SPF) exhibit similar endophenotypic traits as persons with schizophrenia. Less research has compared the relative sensitivity of different endophenotypes in the same sample of individuals with SPF. Fourteen university students with SPF (mean age 20.5+/-1.6; 43% male) and 26 controls (mean age 20.3+/-1.1; 31% male) were defined by the Abbreviated Schizotypal Personality Questionnaire (SPQ-B). All participants reported no known biological relative with schizophrenia. Participants completed three computer-administered cognitive tasks: a 6-min degraded-stimuli A-X Continuous Performance Test (CPT), the Wisconsin Card Sort Test (WCST), and a Span of Apprehension (SOA) task (6- and 12-letter arrays). On the CPT, only omission errors resulted in a statistically significant group difference, U=115.5, p=.05, Cohen's d=0.54 (medium effect size), with the SPF group (mean errors: 3.43+/-3.28) making more omission errors than controls (mean errors: 1.88+/-2.66). Notably, 46% of the controls had no omission errors, compared to 14% of the SPF group. The only SPQ-B factor score to show a statistically significant linear relationship with CPT omission errors was the Cognitive-Perceptual factor (rs=.33, p=.04). Group differences on performance indices from the SOA and WCST did not approach statistical significance. Based on performance from the community-identified schizotypes, results suggest that performance on the CPT may represent a more robust endophenotype of schizophrenia, compared to the SOA and WCST.

Adolescent↗

PubMed2002

The borderline diagnosis III: identifying endophenotypes for genetic studies.

Although it is generally acknowledged that borderline personality disorder (BPD) has a complex, multifactorial etiology with interacting genetic and environmental substrates, the specific genetic underpinnings of this disorder have not been extensively investigated. Family aggregation studies suggest the heritability for BPD as a diagnosis, but the genetic basis for this disorder may be stronger for dimensions such as impulsivity/aggression and affective instability than for the diagnostic criteria itself. Family, adoptive, and twin studies also converge to support an underlying genetic component to the disorder. An endophenotypic approach to defining the genetics of this complex disorder may be called for. Twin studies in an epidemiologic, non-clinically ascertained sample using both diagnostic measures and laboratory measures that can be operationalized, including neuropsychologic, psychophysiologic, and operationalized behavioral tests, may be useful. Large-scale family studies of clinically ascertained samples with careful diagnostic demarcation and measurement of endophenotypes in probands and relatives may also prove to be a promising approach. The use of laboratory paradigms for measures of aggression and affective instability are discussed in the context of such endophenotypic approaches.

Borderline Personality Disorder↗